Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism
While gene mutations in the amyloid precursor protein (APP) and the presenilins lead to an accumulation of the amyloid β-peptide (Aβ) in the brain causing neurodegeneration and familial Alzheimer’s disease (AD), over 95% of all AD cases are sporadic. Despite the pathologies being indistinguishable,...
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doaj-ba6bada48e41427b9919f1512b327ac72020-11-24T22:27:56ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2015-11-01910.3389/fnins.2015.00426163395Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanismCaroline eKerridge0Caroline eKerridge1Daria I. Kozlova2Natalia N Nalivaeva3Natalia N Nalivaeva4Anthony J Turner5University of LeedsEli Lilly and Company LimitedI.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RASUniversity of LeedsI.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RASUniversity of LeedsWhile gene mutations in the amyloid precursor protein (APP) and the presenilins lead to an accumulation of the amyloid β-peptide (Aβ) in the brain causing neurodegeneration and familial Alzheimer’s disease (AD), over 95% of all AD cases are sporadic. Despite the pathologies being indistinguishable, relatively little is known about the mechanisms affecting generation of Aβ in the sporadic cases. Vascular disorders such as ischaemia and stroke are well established risk factors for the development of neurodegenerative diseases and systemic hypoxic episodes have been shown to increase Aβ production and accumulation. We have previously shown that hypoxia causes a significant decrease in the expression of the major Aβ-degrading enzyme neprilysin (NEP) which might deregulate Aβ clearance. Aβ itself is derived from the transmembrane APP along with several other biologically active metabolites including the C-terminal fragment termed the APP intracellular domain (AICD), which regulates the expression of NEP and some other genes in neuronal cells. Here we show that in hypoxia there is a significantly increased expression of caspase-3, 8 and 9 in human neuroblastoma NB7 cells, which can degrade AICD. Using chromatin immunoprecipitation we have revealed that there was also a reduction of AICD bound to the NEP promoter region which underlies the decreased expression and activity of the enzyme under hypoxic conditions. Incubation of the cells with a caspase-3 inhibitor Z-DEVD-FMK could rescue the effect of hypoxia on NEP activity protecting the levels of AICD capable of binding the NEP promoter. These data suggest that activation of caspases might play an important role in regulation of NEP levels in the brain under pathological conditions such as hypoxia and ischemia leading to a deficit of Aβ clearance and increasing the risk of development of AD.http://journal.frontiersin.org/Journal/10.3389/fnins.2015.00426/fullCaspasesNeprilysinhypoxiaAPPAICD |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Caroline eKerridge Caroline eKerridge Daria I. Kozlova Natalia N Nalivaeva Natalia N Nalivaeva Anthony J Turner |
spellingShingle |
Caroline eKerridge Caroline eKerridge Daria I. Kozlova Natalia N Nalivaeva Natalia N Nalivaeva Anthony J Turner Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism Frontiers in Neuroscience Caspases Neprilysin hypoxia APP AICD |
author_facet |
Caroline eKerridge Caroline eKerridge Daria I. Kozlova Natalia N Nalivaeva Natalia N Nalivaeva Anthony J Turner |
author_sort |
Caroline eKerridge |
title |
Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism |
title_short |
Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism |
title_full |
Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism |
title_fullStr |
Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism |
title_full_unstemmed |
Hypoxia affects neprilysin expression through caspase activation and an APP intracellular domain-dependent mechanism |
title_sort |
hypoxia affects neprilysin expression through caspase activation and an app intracellular domain-dependent mechanism |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2015-11-01 |
description |
While gene mutations in the amyloid precursor protein (APP) and the presenilins lead to an accumulation of the amyloid β-peptide (Aβ) in the brain causing neurodegeneration and familial Alzheimer’s disease (AD), over 95% of all AD cases are sporadic. Despite the pathologies being indistinguishable, relatively little is known about the mechanisms affecting generation of Aβ in the sporadic cases. Vascular disorders such as ischaemia and stroke are well established risk factors for the development of neurodegenerative diseases and systemic hypoxic episodes have been shown to increase Aβ production and accumulation. We have previously shown that hypoxia causes a significant decrease in the expression of the major Aβ-degrading enzyme neprilysin (NEP) which might deregulate Aβ clearance. Aβ itself is derived from the transmembrane APP along with several other biologically active metabolites including the C-terminal fragment termed the APP intracellular domain (AICD), which regulates the expression of NEP and some other genes in neuronal cells. Here we show that in hypoxia there is a significantly increased expression of caspase-3, 8 and 9 in human neuroblastoma NB7 cells, which can degrade AICD. Using chromatin immunoprecipitation we have revealed that there was also a reduction of AICD bound to the NEP promoter region which underlies the decreased expression and activity of the enzyme under hypoxic conditions. Incubation of the cells with a caspase-3 inhibitor Z-DEVD-FMK could rescue the effect of hypoxia on NEP activity protecting the levels of AICD capable of binding the NEP promoter. These data suggest that activation of caspases might play an important role in regulation of NEP levels in the brain under pathological conditions such as hypoxia and ischemia leading to a deficit of Aβ clearance and increasing the risk of development of AD. |
topic |
Caspases Neprilysin hypoxia APP AICD |
url |
http://journal.frontiersin.org/Journal/10.3389/fnins.2015.00426/full |
work_keys_str_mv |
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